Dietary and metabolic effects on intestinal stem cells in health and disease
Gehart, H. & Clevers, H. Tales from the crypt: new insights into intestinal stem cells. Nat. Rev. Gastroenterol. Hepatol. 16, 19–34 (2019).
Google Scholar
Lien, E. C. & Vander Heiden, M. G. A framework for examining how diet impacts tumour metabolism. Nat. Rev. Cancer 19, 651–661 (2019).
Google Scholar
Yilmaz, Ö. H. Dietary regulation of the origins of cancer. Sci. Transl. Med. 10, 8–11 (2018).
Google Scholar
Cheng, C.-W. & Yilmaz, Ö. H. 100 years of exploiting diet and nutrition for tissue regeneration. Cell Stem Cell 28, 370–373 (2021).
Google Scholar
The GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med. 377, 13–27 (2017).
Google Scholar
Ng, M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766–781 (2014).
Google Scholar
Mehta, R. S. et al. Dietary patterns and risk of colorectal cancer: analysis by tumor location and molecular subtypes. Gastroenterology 152, 1944–1953.e1 (2017).
Google Scholar
Zaborowski, A. M. et al. Characteristics of early-onset vs late-onset colorectal cancer. JAMA Surg. 156, 865 (2021).
Google Scholar
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).
Google Scholar
Gehart, H. et al. Identification of enteroendocrine regulators by real-time single-cell differentiation mapping. Cell 176, 1158–1173.e16 (2019).
Google Scholar
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
Google Scholar
Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
Google Scholar
Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).
Google Scholar
Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618–623 (2012).
Google Scholar
Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011).
Google Scholar
Wong, V. W. Y. et al. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat. Cell Biol. 14, 401–408 (2012).
Google Scholar
Yan, K. S. et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc. Natl Acad. Sci. USA 109, 466–471 (2012).
Google Scholar
Li, N., Nakauka-Ddamba, A., Tobias, J., Jensen, S. T. & Lengner, C. J. Mouse label-retaining cells are molecularly and functionally distinct from reserve intestinal stem cells. Gastroenterology 151, 298–310.e7 (2016).
Google Scholar
Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915–920 (2008).
Google Scholar
Breault, D. T. et al. Generation of mTert-GFP mice as a model to identify and study tissue progenitor cells. Proc. Natl Acad. Sci. USA 105, 10420–10425 (2008).
Google Scholar
Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).
Google Scholar
Ayyaz, A. et al. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature 569, 121–125 (2019).
Google Scholar
Jadhav, U. et al. Dynamic reorganization of chromatin accessibility signatures during dedifferentiation of secretory precursors into Lgr5+ intestinal stem cells. Cell Stem Cell 21, 65–77.e5 (2017).
Google Scholar
Murata, K. et al. Ascl2-dependent cell dedifferentiation drives regeneration of ablated intestinal stem cells. Cell Stem Cell 26, 377–390.e6 (2020).
Google Scholar
Tan, S. H. et al. A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis. Cell Rep. 34, 108633 (2021).
Google Scholar
Yu, S. et al. Paneth cell multipotency induced by notch activation following injury. Cell Stem Cell 23, 46–59.e5 (2018).
Google Scholar
Jones, J. C. et al. Cellular plasticity of defa4-expressing Paneth cells in response to notch activation and intestinal injury. Cell Mol. Gastroenterol. Hepatol. 7, 533–554 (2019).
Google Scholar
Schmitt, M. et al. Paneth cells respond to inflammation and contribute to tissue regeneration by acquiring stem-like features through SCF/c-Kit signaling. Cell Rep. 24, 2312–2328.e7 (2018).
Google Scholar
de Sousa e Melo, F. & de Sauvage, F. J. Cellular plasticity in intestinal homeostasis and disease. Cell Stem Cell 24, 54–64 (2019).
Google Scholar
van Es, J. H. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat. Cell Biol. 14, 1099–1104 (2012).
Google Scholar
Tetteh, P. W. et al. Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters. Cell Stem Cell 18, 203–213 (2016).
Google Scholar
Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011).
Google Scholar
Farin, H. F. et al. Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature 530, 340–343 (2016).
Google Scholar
Van Es, J. H. et al. Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion. Proc. Natl Acad. Sci. USA 116, 26599–26605 (2019).
Google Scholar
Sasaki, N. et al. Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon. Proc. Natl Acad. Sci. USA 113, E5399–E5407 (2016).
Google Scholar
Kabiri, Z. et al. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development 141, 2206–2215 (2014).
Google Scholar
Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016).
Google Scholar
Wang, Y. et al. Formation of human colonic crypt array by application of chemical gradients across a shaped epithelial monolayer. Cell Mol. Gastroenterol. Hepatol. 5, 113–130 (2018).
Google Scholar
Gjorevski, N. et al. Tissue geometry drives deterministic organoid patterning. Science 375, (2022).
He, S. et al. Stiffness restricts the stemness of the intestinal stem cells and skews their differentiation toward goblet cells. Gastroenterology 164, 1137–1151.e15 (2023).
Google Scholar
Holloway, E. M. et al. Mapping development of the human intestinal niche at single-cell resolution. Cell Stem Cell 28, 568–580.e4 (2021).
Google Scholar
Kinchen, J. et al. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell 175, 372–386.e17 (2018).
Google Scholar
McCarthy, N. et al. Smooth muscle contributes to the development and function of a layered intestinal stem cell niche. Dev. Cell 58, 550–564.e6 (2023).
Google Scholar
McCarthy, N. et al. Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient. Cell Stem Cell 26, 391–402.e5 (2020).
Google Scholar
Kraiczy, J. et al. Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche. Cell Stem Cell 30, 433–449.e8 (2023).
Google Scholar
Greicius, G. et al. PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo. Proc. Natl Acad. Sci. USA 115, E3173–E3181 (2018).
Google Scholar
Niec, R. E. et al. Lymphatics act as a signaling hub to regulate intestinal stem cell activity. Cell Stem Cell 29, 1067–1082.e18 (2022).
Google Scholar
Shoshkes-Carmel, M. et al. Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. Nature 557, 242–246 (2018).
Google Scholar
Bahar Halpern, K. et al. Lgr5+ telocytes are a signaling source at the intestinal villus tip. Nat. Commun. 11, 1936 (2020).
Google Scholar
Goto, N. et al. Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury. Cell Stem Cell 29, 1246–1261.e6 (2022).
Google Scholar
Palikuqi, B. et al. Lymphangiocrine signals are required for proper intestinal repair after cytotoxic injury. Cell Stem Cell 29, 1262–1272.e5 (2022).
Google Scholar
Harnack, C. et al. R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nat. Commun. 10, 4368 (2019).
Google Scholar
Orzechowska-Licari, E. J., Bialkowska, A. B. & Yang, V. W. Sonic Hedgehog and WNT signaling regulate a positive feedback loop between intestinal epithelial and stromal cells to promote epithelial regeneration. Cell Mol. Gastroenterol. Hepatol. 16, 607–642 (2023).
Google Scholar
Huels, D. J. & Sansom, O. J. Stem vs non-stem cell origin of colorectal cancer. Br. J. Cancer 113, 1–5 (2015).
Google Scholar
Varga, J. & Greten, F. R. Cell plasticity in epithelial homeostasis and tumorigenesis. Nat. Cell Biol. 19, 1133–1141 (2017).
Google Scholar
Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992).
Google Scholar
Morin, P. J. et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787–1790 (1997).
Google Scholar
Korinek, V. et al. Constitutive transcriptional activation by a β-catenin–Tcf complex in APC−/− colon carcinoma. Science 275, 1784–1787 (1997).
Google Scholar
van de Wetering, M. et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).
Google Scholar
Sansom, O. J. et al. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 18, 1385–1390 (2004).
Google Scholar
Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).
Google Scholar
Bienz, M. & Clevers, H. Linking colorectal cancer to wnt signaling. Cell 103, 311–320 (2000).
Google Scholar
Huels, D. J. et al. Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells. Nat. Commun. 9, 1132 (2018).
Google Scholar
Flanagan, D. J. et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature 594, 430–435 (2021).
Google Scholar
Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).
Google Scholar
De Sousa, E. et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 543, 676–680 (2017).
Google Scholar
Fumagalli, A. et al. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell 0, 1–10 (2020).
Shimokawa, M. et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 545, 187–192 (2017).
Google Scholar
Ishibashi, F. et al. Contribution of ATOH1+ cells to the homeostasis, repair, and tumorigenesis of the colonic epithelium. Stem Cell Rep. 10, 27–42 (2018).
Google Scholar
Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).
Google Scholar
Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).
Google Scholar
Hilkens, J. et al. RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis. Gut 66, 1095–1105 (2017).
Google Scholar
Davis, H. et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 21, 62–70 (2015).
Google Scholar
Fujii, M. et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18, 827–838 (2016).
Google Scholar
Drost, J. et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature 521, 43–47 (2015).
Google Scholar
Rodríguez-Colman, M. J. et al. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature 543, 424–427 (2017).
Google Scholar
Ludikhuize, M. C. et al. Mitochondria define intestinal stem cell differentiation downstream of a FOXO/notch axis. Cell Metab. 32, 889–900.e7 (2020).
Google Scholar
Berger, E. et al. Mitochondrial function controls intestinal epithelial stemness and proliferation. Nat. Commun. 7, 13171 (2016).
Google Scholar
Rath, E., Moschetta, A. & Haller, D. Mitochondrial function — gatekeeper of intestinal epithelial cell homeostasis. Nat. Rev. Gastroenterol. Hepatol. 15, 497–516 (2018).
Google Scholar
Khaloian, S. et al. Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn’s disease recurrence. Gut 69, 1939–1951 (2020).
Google Scholar
Schell, J. C. et al. Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat. Cell Biol. 19, 1027–1036 (2017).
Google Scholar
Bensard, C. L. et al. Regulation of tumor initiation by the mitochondrial pyruvate carrier. Cell Metab. 31, 284–300.e7 (2020).
Google Scholar
Schell, J. C. et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol. Cell 56, 400–413 (2014).
Google Scholar
Sandoval, I. T. et al. A metabolic switch controls intestinal differentiation downstream of adenomatous polyposis coli (APC). eLife 6, e22706 (2017).
Google Scholar
Sebastian, C. et al. A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine. Nat. Commun. 13, 1503 (2022).
Google Scholar
DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).
Google Scholar
Pavlova, N. N., Zhu, J. & Thompson, C. B. The hallmarks of cancer metabolism: still emerging. Cell Metab. 34, 355–377 (2022).
Google Scholar
Lutz, T. A. & Woods, S. C. Overview of animal models of obesity. Curr. Protoc. Pharmacol. (2012).
Kleinert, M. et al. Animal models of obesity and diabetes mellitus. Nat. Rev. Endocrinol. 14, 140–162 (2018).
Google Scholar
Mah, A. T. et al. Impact of diet-induced obesity on intestinal stem cells: hyperproliferation but impaired intrinsic function that requires insulin/IGF1. Endocrinology 155, 3302–3314 (2014).
Google Scholar
Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).
Google Scholar
Evans, R. M., Barish, G. D. & Wang, Y.-X. PPARs and the complex journey to obesity. Nat. Med. 10, 355–361 (2004).
Google Scholar
Chawta, A., Repa, J. J., Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001).
Google Scholar
Willson, T. M., Brown, P. J., Sternbach, D. D. & Henke, B. R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 43, 527–550 (2000).
Google Scholar
Mana, M. D. et al. High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity. Cell Rep. 35, 109212 (2021).
Google Scholar
Aliluev, A. et al. Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice. Nat. Metab. 3, 1202–1216 (2021).
Google Scholar
Mao, J. et al. Overnutrition stimulates intestinal epithelium proliferation through β-catenin signaling in obese mice. Diabetes 62, 3736–3746 (2013).
Google Scholar
Li, W. et al. The nutritional environment determines which and how intestinal stem cells contribute to homeostasis and tumorigenesis. Carcinogenesis 40, 937–946 (2019).
Google Scholar
Lard. United States Department of Agriculture FoodData Central. USDA (2019).
Oil, Coconut. United States Department of Agriculture FoodData Central. USDA (2019).
Wang, B. et al. Phospholipid remodeling and cholesterol availability regulate intestinal stemness and tumorigenesis. Cell Stem Cell 22, 206–220.e4 (2018).
Google Scholar
Li, Y., Nicholson, R. J. & Summers, S. A. Ceramide signaling in the gut. Mol. Cell Endocrinol. 544, 111554 (2022).
Google Scholar
Summers, S. A., Chaurasia, B. & Holland, W. L. Metabolic messengers: ceramides. Nat. Metab. 1, 1051–1058 (2019).
Google Scholar
Holland, W. L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007).
Google Scholar
Xia, J. Y. et al. Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab. 22, 266–278 (2015).
Google Scholar
Chaurasia, B. et al. Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science 365, 386–392 (2019).
Google Scholar
Li, Y. et al. Ceramides increase fatty acid utilization in intestinal progenitors to enhance stemness and increase tumor risk. Gastroenterology 165, 1136–1150 (2023).
Google Scholar
Yuan, C. et al. Sugar-sweetened beverage and sugar consumption and colorectal cancer incidence and mortality according to anatomic subsite. Am. J. Clin. Nutr. 115, 1481–1489 (2022).
Google Scholar
Joh, H. K. et al. Simple sugar and sugar-sweetened beverage intake during adolescence and risk of colorectal cancer precursors. Gastroenterology 161, 128–142.e20 (2021).
Google Scholar
Taylor, S. R. et al. Dietary fructose improves intestinal cell survival and nutrient absorption. Nature 597, 263–267 (2021).
Google Scholar
Jang, C. et al. The small intestine shields the liver from fructose-induced steatosis. Nat. Metab. 2, 586–593 (2020).
Google Scholar
Willett, W. C., Stampfer, M. J., Colditz, G. A., Rosner, B. A. & Speizer, F. E. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N. Engl. J. Med. 323, 1664–1672 (1990).
Google Scholar
Wasan, H. S., Novelli, M., Bee, J. & Bodmer, W. F. Dietary fat influences on polyp phenotype in multiple intestinal neoplasia mice. Proc. Natl Acad. Sci. USA 94, 3308–3313 (1997).
Google Scholar
Newmark, H. L. et al. A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis 22, 1871–1875 (2001).
Google Scholar
DeClercq, V., McMurray, D. N. & Chapkin, R. S. Obesity promotes colonic stem cell expansion during cancer initiation. Cancer Lett. 369, 336–343 (2015).
Google Scholar
He, T.-C., Chan, T. A., Vogelstein, B. & Kinzler, K. W. PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 99, 335–345 (1999).
Google Scholar
Park, B. H., Vogelstein, B. & Kinzler, K. W. Genetic disruption of PPARδ decreases the tumorigenicity of human colon cancer cells. Proc. Natl Acad. Sci. USA 98, 2598–2603 (2001).
Google Scholar
Gupta, R. A. et al. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-δ accelerates intestinal adenoma growth. Nat. Med. 10, 245–247 (2004).
Google Scholar
Wang, D., Fu, L., Wei, J., Xiong, Y. & DuBois, R. N. PPARδ mediates the effect of dietary fat in promoting colorectal cancer metastasis. Cancer Res. 79, 4480–4490 (2019).
Google Scholar
Barak, Y. et al. Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer. Proc. Natl Acad. Sci. USA 99, 303–308 (2002).
Google Scholar
Saez, E. et al. Activators of the nuclear receptor PPARγ enhance colon polyp formation. Nat. Med. 4, 1058–1061 (1998).
Google Scholar
Lefebvre, A.-M. et al. Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat. Med. 4, 1053–1057 (1998).
Google Scholar
Sarraf, P. et al. Differentiation and reversal of malignant changes in colon cancer through PPARγ. Nat. Med. 4, 1046–1052 (1998).
Google Scholar
Choi, J. et al. Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis. Mol. Cancer Res. 21, 808–824 (2023).
Google Scholar
Choi, J. et al. Intestinal stem cell aging at single-cell resolution: transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics. Aging Cell 22, e13802 (2023).
Google Scholar
Wang, Y. et al. CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene 37, 6025–6040 (2018).
Google Scholar
Beyaz, S. et al. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell 28, 1922–1935.e5 (2021).
Google Scholar
Sun, L., Cai, J. & Gonzalez, F. J. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 18, 335–347 (2021).
Google Scholar
Imray, E. et al. Faecal unconjugated bile acids in patients with colorectal cancer or polyps. Gut 33, 1239–1245 (1992).
Google Scholar
Bayerdorffer, E. et al. Unconjugated secondary bile acids in the serum of patients with colorectal adenomas. Gut 36, 268–273 (1995).
Google Scholar
Mahmoud, N. N. Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis. Carcinogenesis 20, 299–303 (1999).
Google Scholar
Kühn, T. et al. Prediagnostic plasma bile acid levels and colon cancer risk: a prospective study. J. Natl Cancer Inst. 112, 516–524 (2020).
Google Scholar
Dermadi, D. et al. Western diet deregulates bile acid homeostasis, cell proliferation, and tumorigenesis in colon. Cancer Res. 77, 3352–3363 (2017).
Google Scholar
De Gottardi, A. et al. The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig. Dis. Sci. 49, 982–989 (2004).
Google Scholar
Maran, R. R. M. et al. Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. J. Pharmacol. Exp. Ther. 328, 469–477 (2009).
Google Scholar
Modica, S., Murzilli, S., Salvatore, L., Schmidt, D. R. & Moschetta, A. Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res. 68, 9589–9594 (2008).
Google Scholar
Fu, T. et al. FXR regulates intestinal cancer stem cell proliferation. Cell 176, 1098–1112.e18 (2019).
Google Scholar
Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).
Google Scholar
Gonzalez, F. J., Jiang, C. & Patterson, A. D. An intestinal microbiota–farnesoid X receptor axis modulates metabolic disease. Gastroenterology 151, 845–859 (2016).
Google Scholar
Jiang, C. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386–402 (2015).
Google Scholar
Febbraio, M. A. & Karin, M. ‘Sweet death’: fructose as a metabolic toxin that targets the gut–liver axis. Cell Metab. 33, 2316–2328 (2021).
Google Scholar
Goncalves, M. D. et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 363, 1345–1349 (2019).
Google Scholar
Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).
Google Scholar
Lin, S.-J. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002).
Google Scholar
Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span — from yeast to humans. Science 328, 321–326 (2010).
Google Scholar
Weindruch, R., Walford, R. L., Fligiel, S. & Guthrie, D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J. Nutr. 116, 641–654 (1986).
Google Scholar
McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. J. Nutr. 10, 63–79 (1935).
Google Scholar
Yilmaz, Ö. H. et al. MTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).
Google Scholar
Igarashi, M. & Guarente, L. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell 166, 436–450 (2016).
Google Scholar
Mai, V. et al. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res. 63, 1752–1755 (2003).
Google Scholar
Heydari, A. R., Unnikrishnan, A., Lucente, L. V. & Richardson, A. Caloric restriction and genomic stability. Nucleic Acids Res. 35, 7485–7496 (2007).
Google Scholar
Snippert, H. J., Schepers, A. G., Van Es, J. H., Simons, B. D. & Clevers, H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 15, 62–69 (2014).
Google Scholar
Vermeulen, L. et al. Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998 (2013).
Google Scholar
Bruens, L. et al. Calorie restriction increases the number of competing stem cells and decreases mutation retention in the intestine. Cell Rep. 32, 107937 (2020).
Google Scholar
Akagi, K. et al. Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster. PLoS Genet. 14, e1007777 (2018).
Google Scholar
Sasaki, A. et al. Obesity suppresses cell-competition-mediated apical elimination of RasV12-transformed cells from epithelial tissues. Cell Rep. 23, 974–982 (2018).
Google Scholar
de Cabo, R. & Mattson, M. P. Effects of intermittent fasting on health, aging, and disease. N. Engl. J. Med. 381, 2541–2551 (2019).
Google Scholar
Jensen, T. L., Kiersgaard, M. K., Sørensen, D. B. & Mikkelsen, L. F. Fasting of mice: a review. Lab. Anim. 47, 225–240 (2013).
Google Scholar
Pak, H. H. et al. Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. Nat. Metab. 3, 1327–1341 (2021).
Google Scholar
Mitchell, S. J. et al. Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metab. 29, 221–228.e3 (2019).
Google Scholar
Acosta-Rodríguez, V. et al. Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice. Science 376, 1192–1202 (2022).
Google Scholar
Tinkum, K. L. et al. Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival. Proc. Natl Acad. Sci. USA 112, E7148–E7154 (2015).
Google Scholar
Mihaylova, M. M. et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell 22, 769–778.e4 (2018).
Google Scholar
Imada, S. et al. Short term post-fast refeeding enhances intestinal stemness via polyamines. Nature (2024).
Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017).
Google Scholar
Newman, J. C. & Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42–52 (2014).
Google Scholar
Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
Google Scholar
Cheng, C.-W. et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell 178, 1115–1131.e15 (2019).
Google Scholar
Terranova, C. J. et al. Reprogramming of H3K9bhb at regulatory elements is a key feature of fasting in the small intestine. Cell Rep. 37, 110044 (2021).
Google Scholar
Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546.e5 (2017).
Google Scholar
Newman, J. C. et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 26, 547–557.e8 (2017).
Google Scholar
Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018).
Google Scholar
Xia, S. et al. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 25, 358–373 (2017).
Google Scholar
Lien, E. C. et al. Low glycaemic diets alter lipid metabolism to influence tumour growth. Nature 599, 302–307 (2021).
Google Scholar
Dmitrieva-Posocco, O. et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature 605, 160–165 (2022).
Google Scholar
Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).
Google Scholar
Thangaraju, M. et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69, 2826–2858 (2009).
Google Scholar
Mao, T. et al. Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1. Oncogene 42, 1889–1899 (2023).
Google Scholar
Kummerlowe, C. et al. Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation. Sci. Transl. Med. 14, 20 (2022).
Google Scholar
Moore, S. R. et al. Glutamine and alanyl-glutamine promote crypt expansion and mTOR signaling in murine enteroids. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G831–G839 (2015).
Google Scholar
Ueno, P. M. et al. Alanyl-glutamine promotes intestinal epithelial cell homeostasis in vitro and in a murine model of weanling undernutrition. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G612–G622 (2011).
Google Scholar
Louis-Auguste, J. et al. Tryptophan, glutamine, leucine, and micronutrient supplementation improves environmental enteropathy in Zambian adults: a randomized controlled trial. Am. J. Clin. Nutr. 110, 1240–1252 (2019).
Google Scholar
Tran, T. Q. et al. Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer. Nat. Cancer 1, 345–358 (2020).
Google Scholar
Carlberg, C. & Muñoz, A. An update on vitamin D signaling and cancer. Semin. Cancer Biol. 79, 217–230 (2022).
Google Scholar
Gorham, E. D. et al. Optimal vitamin D status for colorectal cancer prevention. Am. J. Prev. Med. 32, 210–216 (2007).
Google Scholar
Peregrina, K. et al. Vitamin D is a determinant of mouse intestinal Lgr5 stem cell functions. Carcinogenesis 36, 25–31 (2015).
Google Scholar
Li, W., Peregrina, K., Houston, M. & Augenlicht, L. H. Vitamin D and the nutritional environment in functions of intestinal stem cells: implications for tumorigenesis and prevention. J. Steroid Biochem. Mol. Biol. 198, 105556 (2020).
Google Scholar
Kennedy, A. R. et al. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am. J. Physiol. Endocrinol. Metab. 292, 1724–1739 (2007).
Google Scholar
Baker, S. A. & Rutter, J. Metabolites as signalling molecules. Nat. Rev. Mol. Cell Biol. 24, 355–374 (2023).
Google Scholar
Mihaylova, M. M., Sabatini, D. M. & Yilmaz, Ö. H. Dietary and metabolic control of stem cell function in physiology and cancer. Cell Stem Cell 14, 292–305 (2014).
Google Scholar
Hamer, H. M. et al. Review article: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27, 104–119 (2007).
Google Scholar
Pryde, S. E., Duncan, S. H., Hold, G. L., Stewart, C. S. & Flint, H. J. The microbiology of butyrate formation in the human colon. FEMS Microbiol. Lett. 217, 133–139 (2002).
Google Scholar
De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010).
Google Scholar
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
Google Scholar
Collins, S. L., Stine, J. G., Bisanz, J. E., Okafor, C. D. & Patterson, A. D. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat. Rev. Microbiol. 21, 236–247 (2023).
Google Scholar
Wahlström, A., Sayin, S. I., Marschall, H.-U. & Bäckhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).
Google Scholar
Jia, W., Xie, G. & Jia, W. Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat. Rev. Gastroenterol. Hepatol. 15, 111–128 (2018).
Google Scholar
Thaiss, C. A. et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science 359, 1376–1383 (2018).
Google Scholar
Chassaing, B., Raja, S. M., Lewis, J. D., Srinivasan, S. & Gewirtz, A. T. Colonic microbiota encroachment correlates with dysglycemia in humans. Cell Mol. Gastroenterol. Hepatol. 4, 205–221 (2017).
Google Scholar
Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).
Google Scholar
Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).
Google Scholar
Pérez, M. M. et al. Interleukin-17/interleukin-17 receptor axis elicits intestinal neutrophil migration, restrains gut dysbiosis and lipopolysaccharide translocation in high-fat diet-induced metabolic syndrome model. Immunology 156, 339–355 (2019).
Google Scholar
Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).
Google Scholar
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Google Scholar
Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007).
Google Scholar
Turnbaugh, P. J., Bäckhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).
Google Scholar
den Besten, G. et al. Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids. Am. J. Physiol. Gastrointest. Liver Physiol. 305, 900–910 (2013).
Google Scholar
Papathanasopoulos, A. & Camilleri, M. Dietary fiber supplements: effects in obesity and metabolic syndrome and relationship to gastrointestinal functions. Gastroenterology 138, 65–72.e2 (2010).
Google Scholar
Dall’Alba, V. et al. Improvement of the metabolic syndrome profile by soluble fibre — guar gum — in patients with type 2 diabetes: a randomised clinical trial. Br. J. Nutr. 110, 1601–1610 (2013).
Google Scholar
Brown, L., Rosner, B., Willett, W. W. & Sacks, F. M. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am. J. Clin. Nutr. 69, 30–42 (1999).
Google Scholar
den Besten, G. et al. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation. Diabetes 64, 2398–2408 (2015).
Google Scholar
Donohoe, D. R. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526 (2011).
Google Scholar
Augenlicht, L. H. et al. Short-chain fatty acid metabolism, apoptosis, and Apc-initiated tumorigenesis in the mouse gastrointestinal mucosa. Cancer Res. 59, 6005–6009 (1999).
Google Scholar
Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).
Google Scholar
Eshleman, E. M. et al. Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity. Immunity 57, 319–332.e6 (2024).
Google Scholar
Zhao, S. et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 579, 586–591 (2020).
Google Scholar
Ang, Q. Y. et al. Ketogenic diets alter the gut microbiome resulting in decreased intestinal TH17 cells. Cell 181, 1263–1275.e16 (2020).
Google Scholar
Shalon, D. et al. Profiling the human intestinal environment under physiological conditions. Nature 617, 581–591 (2023).
Google Scholar
Youm, Y. H. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).
Google Scholar
Goldberg, E. L. et al. β-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep. 18, 2077–2087 (2017).
Google Scholar
Goldberg, E. L. et al. Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue. Nat. Metab. 2, 50–61 (2020).
Google Scholar
Karagiannis, F. et al. Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19. Nature 609, 801–807 (2022).
Google Scholar
Luda, K. M. et al. Ketolysis drives CD8+ T cell effector function through effects on histone acetylation. Immunity 56, 1–15 (2023).
Google Scholar
Zhang, H. et al. Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development. Nat. Cell Biol. 22, 18–25 (2020).
Google Scholar
Biton, M. et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307–1320.e22 (2018).
Google Scholar
Ringel, A. E. et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell 183, 1848–1866.e26 (2020).
Google Scholar
Deng, M. et al. Lepr+ mesenchymal cells sense diet to modulate intestinal stem/progenitor cells via Leptin–Igf1 axis. Cell Res. 32, 670–686 (2022).
Google Scholar
Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N. Engl. J. Med. 389, 514–526 (2023).
Google Scholar
Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).
Google Scholar
Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).
Google Scholar
Heymsfield, S. B. et al. Effect of bimagrumab vs placebo on body fat mass among adults with type 2 diabetes and obesity: a phase 2 randomized clinical trial. JAMA Netw. Open 4, e2033457 (2021).
Google Scholar
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